Morphine sulfate and naltrexone hydrochloride extended release capsules (MS-sNT; EMBEDA®), when crushed and injected, mitigate morphine-induced respiratory depression

Opioid-induced respiratory depression remains a major public health concern. With half of all drug-related deaths due to prescription drug abuse/misuse, respiratory depression is the leading cause of death following a lethal opioid dose. Morphine can induce respiratory depression which may become fatal within 3 hours of an overdose; however, it may be reversed by the timely administration of an opioid antagonist. Unfortunately, timely intervention is not always available. Morphine is often abused intravenously where respiratory depression can occur in minutes. Tampering with morphine sulfate and naltrexone hydrochloride extended release capsules (MS-sNT; EMBEDA®), a unique extended-release morphine formulation with a sequestered naltrexone core, releases both morphine and naltrexone. When both drugs are administered intravenously, naltrexone abates morphine-induced euphoric effects. To our knowledge, the effects on morphine-induced respiratory depression of intravenous administration of morphine and naltrexone in the fixed 25:1 ratio found in MS-sNT have not been previously reported. Results of a single-dose, 3-way crossover study in 28 opioid-experienced, non-dependent men indicated that naltrexone HCl 1.2mg administered intravenously in combination with morphine sulfate 30mg significantly diminished morphine-induced respiratory depression compared with intravenous morphine sulfate 30mg administered alone or normal saline (placebo). Exploratory analyses of End-tidal CO2 (EtCO2) detected statistically significant differences in LS means across all treatment groups for Emax and partial AUEs (p<0.0001). No difference was detected between the combination morphine + naltrexone and placebo groups in EtCO2 levels (p=0.3064), which emphasized naltrexone's pharmacodynamic effect of morphine displacement on the μ-opioid receptor. Results suggest that abuse of Embeda® by extraction and injection may not only abate morphine drug-liking and euphoria but could also mitigate the risk of potentially fatal morphine-induced respiratory depression. The uniqueness of this finding is that the harm reduction potential is already built into the medicine. Supported by King Pharmaceuticals®, Inc.